Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 88469006; ICD10CM: E71.510; ORPHA: 79189, 912; DO: 0080476;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.2 | Peroxisome biogenesis disorder 1A (Zellweger) | 214100 | Autosomal recessive | 3 | PEX1 | 602136 |
A number sign (#) is used with this entry because of evidence that this form of Zellweger syndrome (PBD1A) is caused by homozygous or compound heterozygous mutation in the PEX1 gene (602136) on chromosome 7q21.
Zellweger syndrome is an autosomal recessive systemic disorder characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life (summary by Wanders, 2004).
'Zellweger syndrome' is the prototype of a large group of peroxisomal disorders, which can be classified into 2 main groups: (1) disorders of peroxisome biogenesis and (2) single peroxisomal enzyme deficiencies (see 264470). The peroxisome biogenesis disorders (PBDs) fall into 4 main phenotypic classes. Three of them, Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), have multiple complementation groups and form a spectrum of overlapping features, with the most severe being the Zellweger syndrome and the least severe infantile Refsum disease. The fourth group, rhizomelic chondrodysplasia punctata (RCDP1; 215100), is a distinct PBD phenotype (summary by Moser et al., 1995, Wanders, 2004).
Heimler syndrome, a rare autosomal recessive disorder encompassing sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities, represents a discrete phenotypic entity at the mildest end of the PBD spectrum (Ratbi et al., 2015).
Genetic Heterogeneity of Zellweger Syndrome
Zellweger syndrome (denoted by the suffix 'A' in the symbol) is a genetically heterogeneous disorder and can be caused by mutation in any one of several genes, known as pexins, involved in peroxisome biogenesis. The pexin (PEX) genes encode proteins essential for the assembly of functional peroxisomes (summary by Distel et al., 1996). Forms of Zellweger syndrome include PBD1A, caused by mutation in the PEX1 gene on chromosome 7q21; PBD2A (214110), caused by mutation in the PEX5 (600414) gene on chromosome 12p13; PBD3A (614859), caused by mutation in the PEX12 (601758) gene on chromosome 17; PBD4A (614862), caused by mutation in the PEX6 (601498) gene on chromosome 6p21; PBD5A (614866), caused by mutation in the PEX2 (170993) gene on chromosome 8q21; PBD6A (614870), caused by mutation in the PEX10 (602859) gene on chromosome 1p36; PBD7A (614872), caused by mutation in the PEX26 (608666) gene on chromosome 22q11; PBD8A (614876), caused by mutation in the PEX16 (603360) gene on chromosome 11p12; PBD10A (614882), caused by mutation in the PEX3 (603164) gene on chromosome 6q23-q24; PBD11A (614883), caused by mutation in the PEX13 (601789) gene on chromosome 2p15; PBD12A (614886), caused by mutation in the PEX19 (600279) gene on chromosome 1q22; and PBD13A (614887), caused by mutation in the PEX14 gene (601791) on chromosome 1p36.2.
Mutation in the pexin genes also causes the less severe phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD); see PBD1B (601539) for a phenotypic description and discussion of genetic heterogeneity of these PBDs.
Heimler syndrome-1 (HMLR1; 234580) and -2 (HMLR2; 616617) are caused by mutation in the PEX1 and PEX6 genes, respectively.
The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; 215100), and a PBD without rhizomelia (PBD9B; 614879), are caused by mutation in the PEX7 gene (601757) on chromosome 6q22-q24.
In addition to the defects in peroxisome assembly, Distel et al. (1996) noted that peroxisomal disorders include a number of single peroxisomal enzyme deficiencies: X-linked adrenoleukodystrophy (ALD; 300100), acyl-coenzyme A oxidase deficiency (264470), DHAPAT deficiency (222765), alkyl-DHAP synthase deficiency (600121), glutaric aciduria type III (231690), classic Refsum disease (266500), hyperoxaluria type I (259900), and acatalasia (115500). A peroxisomal and mitochondrial fission defect results in a lethal encephalopathy (EMPF; 614388).
Complementation Groups
Before the nature of the mutations was known, the peroxisomal biogenesis disorders had historically been grouped according to complementation on the basis of cell fusion studies. Complementation groups were assigned numbers (Kennedy-Krieger Institute, Amsterdam University) or letters (Gifu University); various complementation groups proved to be genetically equivalent. Shimozawa et al. (1993) provided a table comparing the complementation groups defined at Gifu University in Japan, Kennedy-Krieger Institute in Baltimore, and Amsterdam University in the Netherlands (Brul et al., 1988). They pointed out that no obvious relationship between genotype and phenotype was found; the clinical phenotype in a single complementation group could be Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease.
Individuals with PBDs of complementation group 1 (CG1, equivalent to CGE) have mutations in the PEX1 gene.
Bowen et al. (1964) described 2 families, each with 2 sibs displaying an unusual malformation syndrome. Cardinal features were failure to thrive, absent or weak sucking and swallowing, finger flexion, congenital glaucoma, malformed ears, small mandible, heart malformations, enlarged clitoris, hypospadias, agenesis of the corpus callosum, and death at an early age. No parental consanguinity was demonstrated in either family, and no chromosomal abnormality was identified. Opitz et al. (1969), who described further cases, suggested that only 1 of the 2 sets of sibs reported by Bowen et al. (1964) (the pair contributed by Zellweger) had the cerebrohepatorenal syndrome; however, in a review, Wanders (2004) noted that both families had Zellweger syndrome. Opitz et al. (1969) suggested the eponymic designation 'Zellweger syndrome,' and made the important observation that serum iron level and iron binding capacity were high in one well-studied case and may provide an easy method for diagnosis of this disorder. A defect in the placental iron transfer mechanism was postulated.
Smith et al. (1965) described a Caucasian brother and sister who died at 8 and 10 weeks of age with aberrant development of the skull, face, ears, eyes, hands and feet, polycystic kidneys with adequate functional renal parenchyma, and intrahepatic biliary dysgenesis. Jaundice developed before death. The karyotype was normal.
Passarge and McAdams (1967) described 5 sisters out of a sibship of 13 with severe, generalized hypotonia and absent Moro response, characteristic craniofacial abnormalities, cortical renal cysts, and hepatomegaly. The brain in 2, studied histologically, showed sudanophilic leukodystrophy. The authors considered this to be the same entity as that reported by Smith et al. (1965) and perhaps the same as that described by Bowen et al. (1964). They proposed 'cerebrohepatorenal syndrome' as an appropriate designation.
Chondral calcification, most marked in the patellas, was a feature pointed out by Poznanski et al. (1970). The change is somewhat like that of chondrodystrophia calcificans congenita. Patton et al. (1972) described 2 cases with the additional feature of thymic anomalies. Abnormalities of iron metabolism were not present. Volpe and Adams (1972) observed a defect in neuronal migration.
Mathis et al. (1978) observed cholestasis in the cerebrohepatorenal syndrome, and electron microscopy of liver biopsy showed mitochondrial abnormalities Pathologic findings were presented by Friedman et al. (1980).
Minor opacities in the ocular lenses in heterozygotes were described by Hittner et al. (1981).
Bleeker-Wagemakers et al. (1986) reported a 13-year-old girl with clinical and biochemical features consistent with Zellweger syndrome. She had severe mental retardation, tapetoretinal degeneration, and sensorineural hearing loss.
Zung et al. (1990) suggested that this disorder was unusually frequent among Karaites in Israel. In addition to dysmyelination, there was also neuronal migration derangements resulting in microgyria/pachygyria, heterotopias, and dysplasias of the inferior olive.
Van Woerden et al. (2006) reviewed the medical charts of 31 Dutch Zellweger spectrum disorder patients with prolonged survival (greater than 1 year). Urinary oxylate excretion was assessed in 23 and glycolate in 22 patients. Hyperoxaluria was present in 19 (83%) and hyperglycolic aciduria in 14 (64%). Pyridoxine treatment in 6 patients did not reduce the oxalate excretion, as in some patients with primary hyperoxaluria type 1 (259900). Renal involvement with urolithiasis and nephrocalcinosis was present in 5, of which 1 developed end-stage renal disease. Van Woerden et al. (2006) concluded that the presence of hyperoxaluria, potentially leading to severe renal involvement, was statistically significantly correlated with the severity of neurologic dysfunction, and that Zellweger spectrum disorder patients should be screened by urinalysis for hyperoxaluria and renal ultrasound for nephrocalcinosis in order to take timely measures to prevent renal insufficiency.
Majewski et al. (2011) reported a patient (patient 2) with PBD1A who presented with Leber congenital amaurosis (see 204000) at 9 months of age. At 20 months of age she had developmental delay, hypotonia, and seizures. Biochemical testing demonstrated elevated C26:0 and C22/C26 very long chain fatty acids and elevated plasma phytanic acid.
Erdem et al. (1995) reported the autopsy finding of intestinal lymphangiectasia in a Turkish 11-day-old girl whose parents were first cousins.
Very-long-chain fatty acids, which are usually oxidized in peroxisomes, were found to accumulate in cultured cells of patients with Zellweger syndrome (Brown et al., 1982)--a feature shared by neonatal adrenoleukodystrophy (see 601539).
Arneson and Ward (1981) studied hyperpipecolic acid in the Zellweger syndrome. Govaerts et al. (1982) reported observations on 16 patients (13 male, 3 female), including 3 pairs of sibs. Ten died before the age of 8 months, and 5 survived beyond age 2 years. Consistent findings were elevated pipecolic acid in serum and cerebrospinal fluid, abnormality of bile acids, and increased urinary excretion of p-OH-phenyl-lactate. Although excretion of pipecolic acid in the urine was not always elevated, the DL-pipecolic acid loading test was always abnormal. They authors concluded that the basic defect was absence or functional disturbance of peroxisomes.
Heymans et al. (1983) showed that tissues of 5 infants who died with Zellweger syndrome contained less than 10% of the normal levels of phosphatidylethanolamine plasmalogen, a major phospholipid of cell membranes. Key enzymes in the synthesis of plasmalogens are known to be located exclusively in the peroxisomes. Moser et al. (1984) demonstrated a 5-fold or greater increase of very-long-chain fatty acid levels, particularly hexacosanoic acid (C26:0) and hexacosenoic acid (C26:1), in plasma and cultured skin fibroblasts in 35 patients. Similar findings in cultured amniocytes permitted prenatal diagnosis. Oxidation of very-long-chain fatty acids, which normally takes place in peroxisomes, was impaired in homogenates of cultured skin fibroblasts and amniocytes. These findings extended the observation that the Zellweger syndrome is a peroxisomal disorder.
Dancis and Hutzler (1986) concluded that hyperpipecolatemia develops postpartum; that plasma pipecolic acid concentrations may not be diagnostic early in life; and that the hyperpipecolatemia plays no etiologic role in the major manifestations of Zellweger disease. Measurements of plasma pipecolic acid in familial hyperlysinemia demonstrated that considerable increases in this substance could be tolerated without evident clinical effect. Pipecolic acid is a minor degradative product of lysine.
Sturk et al. (1987) found that platelet-activating factor (PAF) was absent in 2 Zellweger patients and severely reduced in a third. In all 3 patients, however, the thrombin-induced third mechanism of platelet aggregation was present, indicating that PAF may not be the mediator of the third pathway. PAF synthesis has been reported from stimulation of a large diversity of cell types. PAF is an alkoxyether like the plasmalogens.
Aikawa et al. (1991) presented evidence for the existence of low-density catalase-containing particles in both normal and Zellweger syndrome fibroblasts. Thus, catalase is not free in the cytosol of Zellweger syndrome fibroblasts as commonly thought, but in particles (W particles). Aikawa et al. (1991) found that L-alpha-hydroxyacid oxidase, another peroxisomal matrix enzyme, is also present in W particles derived from normal and Zellweger syndrome fibroblasts. Mayatepek et al. (1993) found that urinary excretion of leukotriene E4 (LTE4) and N-acetyl-LTE4, relative to creatinine, was increased more than 10-fold in 8 patients with Zellweger syndrome in comparison to healthy infants. The increased levels of these biologically active, proinflammatory mediators might be of pathophysiologic significance in this disorder. Furthermore, the pronounced urinary excretion of omega-carboxy-LTE4, omega-carboxy-LTB4, and LTB4 may be of diagnostic value.
By administering tritiated prostaglandin F(2-alpha) to an infant with Zellweger syndrome, Diczfalusy et al. (1991) found that the patient excreted considerably less polar metabolites of prostaglandin in the urine than did control subjects. The major urinary metabolite found in control subjects was almost absent in the urine from the Zellweger patient. The study indicated that peroxisomal beta-oxidation is of major importance for in vivo chain shortening of prostaglandins.
Complementation Studies
Brul et al. (1988) used complementation analysis after somatic cell fusion to study the genetic relationships among various disorders with simultaneous impairment of several peroxisomal functions, including several forms of Zellweger syndrome, rhizomelic chondrodysplasia punctata (see 215100), infantile Refsum disease, and neonatal adrenoleukodystrophy. As an index of complementation they used the activity of acyl-coenzyme A:dihydroxyacetonephosphate acyltransferase, which is deficient in these diseases. At least 5 complementation groups were identified, indicating marked genetic heterogeneity.
Poll-The et al. (1989) did complementation studies using the production of (14)CO(2) from exogenous labeled phytanic acid in fibroblast monolayers from patients with classic Refsum disease and peroxisomal disorders. Absence of complementation was found between Zellweger syndrome and infantile Refsum disease after polyethylene glycol fusion of cells from patients with the 2 disorders. Classic Refsum disease, rhizomelic chondrodysplasia punctata, and neonatal adrenoleukodystrophy all complemented one another and complemented Zellweger syndrome or infantile Refsum disease lines. Four complementation groups were recognized, reflecting the involvement of at least 4 genes in phytanic acid alpha-oxidation, including those with regulatory and assembly roles.
Goldfischer et al. (1973) presented evidence of abnormality in peroxisomes and mitochondria, the 2 organelles principally concerned with cellular respiration. Versmold et al. (1977) found absence of peroxisomes in the liver of 3 patients with Zellweger syndrome.
Danks et al. (1975) found elevated levels of pipecolic acid in blood and urine and suggested that a defect in metabolism of pipecolic acid might be at the root of the disorder. Piperidine, a product of pipecolic acid, is involved in hibernation.
The findings of Hanson et al. (1979) supported the hypothesis of defective mitochondrial oxidation in the Zellweger syndrome.
Govaerts et al. (1982) concluded that the basic defect was absence or functional disturbance of peroxisomes, based on the biochemical profiles of patients.
Santos et al. (1985) showed that Zellweger fibroblasts also lacked peroxisomes. Furthermore, catalase and fatty acyl-CoA oxidase, although present, behaved as cytosolic enzymes. They interpreted these findings to indicate that the defect in Zellweger syndrome resides in the assembly of the peroxisomal constituents.
According to Moser (1986), 5 enzymatic defects had been demonstrated or deduced in Zellweger syndrome, although none appeared to be the primary defect. The 5 were dihydroxyacetone phosphate acyltransferase (involved in synthesis of plasmalogen); peroxisomal fatty acid beta-oxidation (same as in adrenoleukodystrophy; 300100); phytanic acid oxidase (same as in Refsum syndrome; 266500); degradation of pipecolic acid; and processing of bile acid intermediates.
In reporting accumulation of very-long-chain fatty acids in these disorders, Poulos et al. (1986) commented that in Zellweger syndrome and possibly in infantile Refsum syndrome (see 601539), the defect in beta-oxidation may be secondary to a primary defect in the structure and/or function of peroxisomes, while in X-linked adrenoleukodystrophy it resides in a pathway specific for oxidation of very-long-chain fatty acids.
Wanders et al. (1987) presented evidence that peroxisomes contain at least 2 fatty acid-activating enzyme systems, one that activates long chain fatty acids such as palmitate, and a second that is responsible for the activation of very-long-chain fatty acids such as lignocerate and cerotate. The peroxisomal oxidation of all 3 fatty acid substrates was markedly deficient in fibroblasts from patients with Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, in accordance with the deficiency of peroxisomes in these patients. In fibroblasts from patients with X-linked adrenoleukodystrophy, the peroxisomal oxidation of lignocerate and cerotate was impaired, but not that of palmitate. Very long chain fatty acid synthetase was present not only in peroxisomes but also in microsomes. The evidence led Wanders et al. (1987) to conclude that X-linked adrenoleukodystrophy (300100) was caused by deficiency of peroxisomal very-long-chain fatty acyl-CoA synthetase.
Santos et al. (1988) demonstrated that although peroxisomes were apparently missing in Zellweger syndrome, peroxisomal membrane proteins could be identified by immunofluorescence microscopy. In control fibroblasts, peroxisomes appeared as small dots. In Zellweger fibroblasts, the peroxisomal membrane proteins were located in unusual empty membrane structures of larger size. Santos et al. (1988) suggested, therefore, that the primary defect was in the mechanism for import of matrix proteins.
Pristanic acid is the product of the first step in the degradation of phytanic acid. Both phytanic acid and pristanic acid accumulate in Zellweger syndrome. Wanders et al. (1990) demonstrated that the cause of the accumulation was deficiency of pristanoyl-CoA oxidase. Thus, the previously held view that pristanic acid beta-oxidation occurs in mitochondria was disproved.
Wilson et al. (1986) used measurement of dihydroxyacetone phosphate acyltransferase, a peroxisomal enzyme, as a diagnostic method in Zellweger syndrome.
Prenatal Diagnosis
Lazarow et al. (1988) showed that in homogenates of Zellweger syndrome amniocytes, catalase remains in the supernatant on sedimentation, whereas in normal cells, catalase sediments with the peroxisomes. The difference was unambiguous and reproducible and provided a simple method for prenatal diagnosis.
Naritomi et al. (1988) found a microdeletion of chromosome 7 in an infant with Zellweger syndrome. The deletion involved 7q11.12-q11.23. They suggested that the Zellweger gene is situated in this region. Naritomi et al. (1989) reported a second case of Zellweger syndrome with a rearrangement of chromosome 7: a pericentric inversion, inv(7)(p12q11.23). They suggested that this confirms the assignment to 7q11, probably 7q11.23.
Moser et al. (1995) found that among the 61 patients in complementation group 1 (corresponding to Netherlands group 2 and Japan group E), 56% had the Zellweger syndrome phenotype, 26% had the phenotype of neonatal adrenoleukodystrophy (NALD; see 601539), 11% had the phenotype of infantile Refsum disease (IRD; see 601539), and 43 patients (25%) had phenotype of rhizomelic chondrodysplasia (RCDP1; 215100). A variant phenotype was observed in 7% of patients.
Reuber et al. (1997) found that expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 patients with peroxisomal biogenesis disorders of complementation group 1 (CG1). Additionally, they detected PEX1 mutations in multiple CG1 probands (see, e.g., 602136.0001).
Portsteffen et al. (1997) identified 3 mutant alleles in CG1 patients. One of these, a G-to-A transition in exon 15 resulting in G843D (602136.0001), was found in homozygosity in 1 patient and heterozygosity in another.
Tamura et al. (1998) demonstrated that human PEX1 expression restored peroxisomal protein import in fibroblasts from 3 patients with Zellweger syndrome and neonatal adrenoleukodystrophy of complementation group 1, which is the peroxisome biogenesis disorder (PBD) of highest incidence. Tamura et al. (1998) found that a patient with Zellweger syndrome was a compound heterozygote for 2 inactivating mutations of the PEX1 gene (602136.0002, 602136.0003). The cDNAs corresponding to these PEX1 mutations were defective in peroxisome-restoring activity when expressed in the patient's fibroblasts as well as in ZP107 cells. This method of identifying PEX1 cDNA complemented that used by Reuber et al. (1997) and Portsteffen et al. (1997), who isolated the human PEX1 gene by a homology search of a human EST database using a yeast PEX1 sequence. All 3 studies demonstrated unequivocally that PEX1 is the causative gene for complementation group 1 peroxisomal disorders.
In a patient (patient 2) with PBD1A, Majewski et al. (2011) identified compound heterozygous mutations in the PEX1 gene (G843D, 602136.0001; c.2098insT, 602136.0011).
Reviews
Subramani (1997) summarized the progress in identifying PEX genes responsible for human genetic diseases. Waterham and Cregg (1997) reviewed the current understanding of peroxisome biogenesis.
Ebberink et al. (2011) reported the results of genetic complementation studies in more than 600 cell lines from patients with a Zellweger syndrome spectrum disorder. They provided an overview of all mutations identified in these cell lines as well as previously reported mutations in respective PEX genes. No novel genetic complementation groups were identified, suggesting that all PEX gene defects resulting in peroxisome deficiency are known.
Using gene targeting, Li et al. (2002) generated mice lacking peroxisome biogenesis factor 11B (Pex11b; 603867). Mouse models generated by disruption of Pex5 (600414) or Pex2 (170993), Pex11b knockout mice displayed many pathologic hallmarks similar to Zellweger syndrome mouse models generated by disruption of Pex5 or Pex2, including a neuronal migration defect, enhanced neuronal apoptosis, a developmental delay, neonatal hypotonia, and neonatal lethality. However, Pex11b-deficient mice did not display the peroxisomal enzyme import defects that are the cellular hallmarks of this disease. The results demonstrated that the neuropathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenged models of Zellweger syndrome pathogenesis. Li et al. (2002) concluded that Pex11b deficiency represents a novel peroxisomal disorder that mimics major neurologic and developmental pathologic features of Zellweger syndrome but lacks many of its cellular and biochemical features.
The complementation studies by somatic cell fusion by Brul et al. (1988) suggested the existence of several forms of Zellweger syndrome. Shimozawa et al. (1993) indicated the existence of at least 9 groups of peroxisome-deficient disorders identified by somatic cell fusion studies. For the most part, there was no clear relationship between genotype and phenotype. The phenotype in cases of the same complementation group could be Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease.
Peroxisome biogenesis disorders (PBDs) include Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy, and classic rhizomelic chondrodysplasia punctata (RCDP1). Somatic cell fusion complementation analysis indicated that the PBDs can be caused by defects in at least 11 different genes (Shimozawa et al., 1993; Moser et al., 1995). Because these disorders are associated with a peroxisomal protein sorting defect, a major focus of PBD research had been on the elucidation of the molecular mechanisms of protein import into peroxisomes.
In a child with a degenerative neurologic disease and hepatomegaly, Gatfield et al. (1968) found grossly elevated blood concentrations of pipecolic acid with mild generalized amino aciduria. Pipecolic acid is an intermediate in lysine catabolism. However, the patient showed no delay in clearing lysine from the blood, indicating, as does other evidence, that the main lysine catabolic pathway is not via pipecolic acid. Autopsy revealed widespread demyelination in the central nervous system. Arneson et al. (1982) reported a female infant who showed the clinical presentation of Zellweger syndrome. Pipecolic acid was increased in plasma and urine. She showed reduced clearance of an administered load of pipecolic acid. Govaerts et al. (1982) expressed the opinion that these cases had the Zellweger syndrome since hyperpipecolic acidemia is a feature of that disorder.
Burton et al. (1981) reported 2 brothers with hyperpipecolatemia. The clinical features closely resembled those of Zellweger syndrome; however, electron microscopy showed presence of hepatic peroxisomes. A functional disorder of peroxisomes may have been present in these cases.
Kelley (1983) discussed the relationship between Zellweger syndrome and hyperpipecolatemia. Are there any cases of hyperpipecolatemia that are not Zellweger syndrome? Kelley (1984) suspected that several different genetic defects can lead to hyperpipecolatemia and that Zellweger syndrome, which itself may be heterogeneous, is only one of these. The complementation studies of Brul et al. (1988) suggested that hyperpipecolic acidemia is allelic to one form of Zellweger syndrome and with the infantile form of Refsum syndrome.
Moser (1998) indicated that most patients with hyperpipecolatemia, including the original case of Thomas et al. (1975) (see 614879), are part of the Zellweger-neonatal adrenoleukodystrophy-infantile Refsum continuum. Some cases are associated with high phytanic acid and pristanic acid and represent a different, and not yet fully defined, genetic peroxisomal disorder. In other cases, hyperpipecolatemia may reflect nongenetic liver or kidney disease. Moser (1998) stated that he was uncertain whether isolated, genetically determined hyperpipecolatemia exists.
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